Pathogenic, glycolytic PD-1+ B cells accumulate in the hypoxic RA joint

JCI Insight. 2020 Nov 5;5(21):e139032. doi: 10.1172/jci.insight.139032.


While autoantibodies are used in the diagnosis of rheumatoid arthritis (RA), the function of B cells in the inflamed joint remains elusive. Extensive flow cytometric characterization and SPICE algorithm analyses of single-cell synovial tissue from patients with RA revealed the accumulation of switched and double-negative memory programmed death-1 receptor-expressing (PD-1-expressing) B cells at the site of inflammation. Accumulation of memory B cells was mediated by CXCR3, evident by the observed increase in CXCR3-expressing synovial B cells compared with the periphery, differential regulation by key synovial cytokines, and restricted B cell invasion demonstrated in response to CXCR3 blockade. Notably, under 3% O2 hypoxic conditions that mimic the joint microenvironment, RA B cells maintained marked expression of MMP-9, TNF, and IL-6, with PD-1+ B cells demonstrating higher expression of CXCR3, CD80, CD86, IL-1β, and GM-CSF than their PD-1- counterparts. Finally, following functional analysis and flow cell sorting of RA PD-1+ versus PD-1- B cells, we demonstrate, using RNA-Seq and emerging fluorescence lifetime imaging microscopy of cellular NAD, a significant shift in metabolism of RA PD-1+ B cells toward glycolysis, associated with an increased transcriptional signature of key cytokines and chemokines that are strongly implicated in RA pathogenesis. Our data support the targeting of pathogenic PD-1+ B cells in RA as a focused, novel therapeutic option.

Keywords: B cells; Cell Biology; Metabolism; Rheumatology; hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Case-Control Studies
  • Glycolysis*
  • Humans
  • Hypoxia / physiopathology*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Programmed Cell Death 1 Receptor / immunology*
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, CXCR3
  • Synovial Membrane / immunology*
  • Synovial Membrane / metabolism


  • CXCR3 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, CXCR3